Publications by authors named "Jane Armitage"

84 Publications

The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs.

Health Technol Assess 2021 Mar;25(16):1-62

Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

Background: Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis.

Objectives: To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related.

Design: A series of 200 double-blinded N-of-1 trials.

Setting: Participants were recruited from 50 general practices in England and Wales.

Participants: Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms.

Interventions: Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo.

Main Outcome Measures: The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant's belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant's decision about statin treatment following the trial, and whether or not they found their own trial result helpful.

Results: A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14;  = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods.

Conclusions: Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial.

Future Work: We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications.

Limitations: This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations.

Trial Registration: Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 16. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020196PMC
March 2021

A Biomarker-based Biological Age in UK Biobank: Composition and Prediction of Mortality and Hospital Admissions.

J Gerontol A Biol Sci Med Sci 2021 Jun;76(7):1295-1302

Nuffield Department of Population Health, University of Oxford, UK.

Background: Chronological age is the strongest risk factor for most chronic diseases. Developing a biomarker-based age and understanding its most important contributing biomarkers may shed light on the effects of age on later-life health and inform opportunities for disease prevention.

Methods: A subpopulation of 141 254 individuals healthy at baseline were studied, from among 480 019 UK Biobank participants aged 40-70 recruited in 2006-2010, and followed up for 6-12 years via linked death and secondary care records. Principal components of 72 biomarkers measured at baseline were characterized and used to construct sex-specific composite biomarker ages using the Klemera Doubal method, which derived a weighted sum of biomarker principal components based on their linear associations with chronological age. Biomarker importance in the biomarker ages was assessed by the proportion of the variation in the biomarker ages that each explained. The proportions of the overall biomarker and chronological age effects on mortality and age-related hospital admissions explained by the biomarker ages were compared using likelihoods in Cox proportional hazard models.

Results: Reduced lung function, kidney function, reaction time, insulin-like growth factor 1, hand grip strength, and higher blood pressure were key contributors to the derived biomarker age in both men and women. The biomarker ages accounted for >65% and >84% of the apparent effect of age on mortality and hospital admissions for the healthy and whole populations, respectively, and significantly improved prediction of mortality (p < .001) and hospital admissions (p < 1 × 10-10) over chronological age alone.

Conclusions: This study suggests that a broader, multisystem approach to research and prevention of diseases of aging warrants consideration.
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http://dx.doi.org/10.1093/gerona/glab069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202154PMC
June 2021

Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials.

BMJ 2021 02 24;372:n135. Epub 2021 Feb 24.

Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

Objective: To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins.

Design: Series of randomised, placebo controlled n-of-1 trials.

Setting: Primary care across 50 sites in the United Kingdom, December 2016 to April 2018.

Participants: 200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms.

Interventions: Participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo.

Main Outcome Measures: At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods.

Results: 151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins.

Conclusions: No overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment.

Trial Registration: ISRCTN30952488, EUDRACT 2016-000141-31, NCT02781064.
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http://dx.doi.org/10.1136/bmj.n135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903384PMC
February 2021

Comparison of four methods to measure haemoglobin concentrations in whole blood donors (COMPARE): A diagnostic accuracy study.

Transfus Med 2021 Apr 20;31(2):94-103. Epub 2020 Dec 20.

Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Objective: To compare four haemoglobin measurement methods in whole blood donors.

Background: To safeguard donors, blood services measure haemoglobin concentration in advance of each donation. NHS Blood and Transplant's (NHSBT) customary method have been capillary gravimetry (copper sulphate), followed by venous spectrophotometry (HemoCue) for donors failing gravimetry. However, NHSBT's customary method results in 10% of donors being inappropriately bled (ie, with haemoglobin values below the regulatory threshold).

Methods: We compared the following four methods in 21 840 blood donors (aged ≥18 years) recruited from 10 NHSBT centres in England, with the Sysmex XN-2000 haematology analyser, the reference standard: (1) NHSBT's customary method; (2) "post donation" approach, that is, estimating current haemoglobin concentration from that measured by a haematology analyser at a donor's most recent prior donation; (3) "portable haemoglobinometry" (using capillary HemoCue); (4) non-invasive spectrometry (using MBR Haemospect or Orsense NMB200). We assessed sensitivity; specificity; proportion who would have been inappropriately bled, or rejected from donation ("deferred") incorrectly; and test preference.

Results: Compared with the reference standard, the methods ranged in test sensitivity from 17.0% (MBR Haemospect) to 79.0% (portable haemoglobinometry) in men, and from 19.0% (MBR Haemospect) to 82.8% (portable haemoglobinometry) in women. For specificity, the methods ranged from 87.2% (MBR Haemospect) to 99.9% (NHSBT's customary method) in men, and from 74.1% (Orsense NMB200) to 99.8% (NHSBT's customary method) in women. The proportion of donors who would have been inappropriately bled ranged from 2.2% in men for portable haemoglobinometry to 18.9% in women for MBR Haemospect. The proportion of donors who would have been deferred incorrectly with haemoglobin concentration above the minimum threshold ranged from 0.1% in men for NHSBT's customary method to 20.3% in women for OrSense. Most donors preferred non-invasive spectrometry.

Conclusion: In the largest study reporting head-to-head comparisons of four methods to measure haemoglobin prior to blood donation, our results support replacement of NHSBT's customary method with portable haemoglobinometry.
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http://dx.doi.org/10.1111/tme.12750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048787PMC
April 2021

Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom.

Eur Heart J 2020 09;41(35):3336-3342

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute, University of Oxford, Old Road Campus, Oxford OX3 7LF, UK.

Aims: Statins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom.

Methods And Results: An observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73-92.69, P across thirds = 9·1 × 10-48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms.

Conclusions: The absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms.
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http://dx.doi.org/10.1093/eurheartj/ehaa574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544537PMC
September 2020

Use of Run-in Periods in Randomized Trials.

JAMA 2020 Jul;324(2):188-189

Nuffield Department of Population Health, MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, United Kingdom.

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http://dx.doi.org/10.1001/jama.2020.6463DOI Listing
July 2020

Effects of Omega-3 Fatty Acid Supplements on Arrhythmias.

Circulation 2020 01 27;141(4):331-333. Epub 2020 Jan 27.

Medical Research Council Population Health Research Unit (S.P., R.H., L.B., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044165DOI Listing
January 2020

Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis.

JAMA Netw Open 2019 12 2;2(12):e1917789. Epub 2019 Dec 2.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Importance: Vitamin D and calcium supplements are recommended for the prevention of fracture, but previous randomized clinical trials (RCTs) have reported conflicting results, with uncertainty about optimal doses and regimens for supplementation and their overall effectiveness.

Objective: To assess the risks of fracture associated with differences in concentrations of 25-hydroxyvitamin D (25[OH]D) in observational studies and the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs.

Data Sources: PubMed, EMBASE, Cochrane Library, and other RCT databases were searched from database inception until December 31, 2018. Searches were performed between July 2018 and December 2018.

Study Selection: Observational studies involving at least 200 fracture cases and RCTs enrolling at least 500 participants and reporting at least 10 incident fractures were included. Randomized clinical trials compared vitamin D or vitamin D and calcium with control.

Data Extraction And Synthesis: Two researchers independently extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and assessed possible bias. Rate ratios (RRs) were estimated using fixed-effects meta-analysis. Data extraction and synthesis took place between July 2018 and June 2019.

Main Outcomes And Measures: Any fracture and hip fracture.

Results: In a meta-analysis of 11 observational studies (39 141 participants, 6278 fractures, 2367 hip fractures), each increase of 10.0 ng/mL (ie, 25 nmol/L) in 25 (OH)D concentration was associated with an adjusted RR for any fracture of 0.93 (95% CI, 0.89-0.96) and an adjusted RR for hip fracture of 0.80 (95% CI, 0.75-0.86). A meta-analysis of 11 RCTs (34 243 participants, 2843 fractures, 740 hip fractures) of vitamin D supplementation alone (daily or intermittent dose of 400-30 000 IU, yielding a median difference in 25[OH]D concentration of 8.4 ng/mL) did not find a reduced risk of any fracture (RR, 1.06; 95% CI, 0.98-1.14) or hip fracture (RR, 1.14; 95% CI, 0.98-1.32), but these trials were constrained by infrequent intermittent dosing, low daily doses of vitamin D, or an inadequate number of participants. In contrast, a meta-analysis of 6 RCTs (49 282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with vitamin D (daily doses of 400-800 IU, yielding a median difference in 25[OH]D concentration of 9.2 ng/mL) and calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture (RR, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk of hip fracture (RR, 0.84; 95% CI, 0.72-0.97).

Conclusions And Relevance: In this systematic review and meta-analysis, neither intermittent nor daily dosing with standard doses of vitamin D alone was associated with reduced risk of fracture, but daily supplementation with both vitamin D and calcium was a more promising strategy.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.17789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991219PMC
December 2019

Investigating modifications to participant information materials to improve recruitment into a large randomized trial.

Trials 2019 Dec 5;20(1):681. Epub 2019 Dec 5.

MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Large randomized trials are the best method to test the efficacy and safety of treatments expected to have moderate effects. We observed a significant decline in potential participants' response to mailed invitations to participate in such trials over a 10-year period and investigated possible reasons behind this and potential modifications to the invitation process to mitigate it.

Methods: Participants who declined to participate in the HPS2-THRIVE trial were asked to give a reason. Formal focus groups were conducted to explore the reasons that potential participants might have for not participating. In addition, two embedded randomized comparisons around the timing of provision of the full participant information leaflet (PIL) and its style were conducted during recruitment into this large randomized trial. HPS2-THRIVE is registered at ClinicalTrials.gov (NCT00461630).

Results: The commonest reason given for declining invitations related to mobility and transportation (despite the offer of travel expenses). Both the focus groups and potential participants who declined their invitation indicated concern about side-effects of the treatment (as presented in the PIL) as a reason for declining the invitation. Neither delaying provision of the full PIL until the potential participant attended the trial clinic, nor modifying the style of the PIL improved the proportion of potential participants entering the trial: odds ratio (OR) 1.05 (95% confidence interval (CI) 0.94-1.17) and 1.10 (95% CI 0.94-1.28), respectively. However, modifying the style of the PIL did increase the proportion of participants attending screening appointments (OR 1.17, 95% CI 1.03-1.33).

Conclusions: Many reasons given for not participating in trials are not tractable to individual trials. However, modification of the PIL does show potential to modestly improve participation. If further trials could identify similar simple interventions that were beneficial, their net effects could substantially improve trial participation and facilitate recruitment into large trials.
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http://dx.doi.org/10.1186/s13063-019-3779-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896768PMC
December 2019

Streamlined mail-based methods for large randomised trials: lessons learnt from the ASCEND study.

Diabetologia 2020 05 30;63(5):898-905. Epub 2019 Nov 30.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, UK.

Reliable assessment of the effects of an intervention usually requires large randomised trials but such studies are becoming increasingly complex and costly to run. 'Streamlined' trials are needed in which every aspect of the trial design and conduct is simplified, retaining only those elements needed to answer the research question and ensure the safety of the individual participants. In this review we discuss how the trial 'A Study of Cardiovascular Events iN Diabetes' (ASCEND) was streamlined. The study included a two-by-two factorial design: it assessed the effects of low-dose aspirin and, separately, supplementation with n-3 fatty acids on serious vascular events in 15,480 people with diabetes but no overt cardiovascular disease. Other key streamlined design features, such as mail-based recruitment and follow-up, mainly by post, with no in-person visits and use of a run-in period, are also described. We go on to discuss the success of the study and other studies that have employed a similar mail-based approach, and the type of clinical trials that are suitable for mail-based design. Finally, we consider the limitations of the study, and how these could be circumvented in future studies. ASCEND randomised large numbers of eligible participants, achieved good adherence rates and almost complete follow-up at a fraction of the cost of traditional clinic-based trials. Such studies are necessary if researchers are to address the important clinical questions most relevant to improving health.
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http://dx.doi.org/10.1007/s00125-019-05049-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145772PMC
May 2020

Serious Adverse Effects of Extended-release Niacin/Laropiprant: Results From the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial.

Clin Ther 2019 09 22;41(9):1767-1777. Epub 2019 Aug 22.

MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Purpose: The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial of patients at high risk of vascular disease found that adding extended-release niacin-laropiprant to intensive statin-based LDL-lowering therapy had no benefit on cardiovascular outcomes. However, the trial also identified previously unrecognized serious adverse effects (including new-onset diabetes, bleeding, and infection). Our objective was to explore the safety profile of niacin-laropiprant and examine whether any patients were at lower (or higher) risk of its adverse effects.

Methods: HPS2-THRIVE was a randomized, double-blind trial of niacin-laropiprant (2000/40 mg/d) versus placebo among 25,673 patients at high risk of vascular disease. Information on all serious adverse events was collected during a median of 3.9 years of study treatment. Effects of niacin-laropiprant on new-onset diabetes, disturbances of diabetes control, bleeding, infection, and gastrointestinal upset were estimated by (1) time after randomization, (2) severity, (3) baseline characteristics, (4) baseline risk of the adverse event of interest, and (5) risk of major vascular event.

Findings: The hazard ratio (HR) for new-onset diabetes with niacin/laropiprant was 1.32 (95% CI, 1.16-1.51; P < .001), which corresponded to an absolute excess of 4 people (95% CI, 2-6) developing diabetes per 1000 person-years in the study population as a whole. Among the 8299 participants with diabetes at baseline, the HR for serious disturbances in diabetes control was 1.56 (95% CI, 1.35-1.80), corresponding to an absolute excess of 12 (95% CI, 8-16) per 1000 person-years. The HR was 1.38 (95% CI, 1.17-1.63; P < .001) for serious bleeding, corresponding to an absolute excess of 2 (95% CI, 1-3) per 1000 person-years and 1.22 (95% CI, 1.11-1.34; P < .001) for serious infection, corresponding to an absolute excess of 4 (95% CI, 2-6) per 1000 person-years. The excess risks of these serious adverse events were larger in the first year after starting niacin-laropiprant therapy than in later years (except for the excess of infection, which did not appear to attenuate with time), and the risks of nonfatal and fatal events were similarly increased. The absolute excesses of each of these adverse effects were similar regardless of the baseline risk of the outcome.

Implications: Practitioners or patients considering the use of niacin (in addition to, or instead of, a statin) despite the lack of evidence of cardiovascular benefits (at least when added to effective statin therapy) should take account of the significant risks of these serious adverse effects when making such decisions. ClinicalTrials.gov identifier: NCT00461630.
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http://dx.doi.org/10.1016/j.clinthera.2019.06.012DOI Listing
September 2019

Longer-term efficiency and safety of increasing the frequency of whole blood donation (INTERVAL): extension study of a randomised trial of 20 757 blood donors.

Lancet Haematol 2019 Oct 2;6(10):e510-e520. Epub 2019 Aug 2.

Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Strangeways Research Laboratory, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK; British Heart Foundation Cambridge Centre for Research Excellence, Addenbrooke's Hospital, Cambridge, UK.

Background: The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments.

Methods: The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed.

Findings: Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7-1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04-0·17; p=0·0003) in men and 0·06 units per year (0·01-0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21-0·25) in men and 0·14 units per year (0·12-0·15) in women (both p<0·0001). More frequent donation resulted in more deferrals for low haemoglobin (odds ratio per week shorter inter-donation interval 1·19 [95% CI 1·15-1·22] in men and 1·10 [1·06-1·14] in women), and lower mean haemoglobin (difference per week shorter inter-donation interval -0·84 g/L [95% CI -0·99 to -0·70] in men and -0·45 g/L [-0·59 to -0·31] in women) and ferritin concentrations (percentage difference per week shorter inter-donation interval -6·5% [95% CI -7·6 to -5·5] in men and -5·3% [-6·5 to -4·2] in women; all p<0·0001). No differences were observed in quality of life, serious adverse events, or self-reported symptoms (p>0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p<0·0001).

Interpretation: During a period of up to 4 years, shorter inter-donation intervals and more intensive reminders resulted in more blood being collected without a detectable effect on donors' mental and physical wellbeing. However, donors had decreased haemoglobin concentrations and more self-reported symptoms compared with the initial 2 years of the trial. Our findings suggest that blood collection services could safely use shorter donation intervals and more intensive reminders to meet shortages, for donors who maintain adequate haemoglobin concentrations and iron stores.

Funding: NHS Blood and Transplant, UK National Institute for Health Research, UK Medical Research Council, and British Heart Foundation.
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http://dx.doi.org/10.1016/S2352-3026(19)30106-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029279PMC
October 2019

Comment on Kim et al. The Effect of a Smartphone-Based, Patient-Centered Diabetes Care System in Patients With Type 2 Diabetes: A Randomized, Controlled Trial for 24 Weeks. Diabetes Care 2019;42:3-9.

Diabetes Care 2019 07;42(7):e125

Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.

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http://dx.doi.org/10.2337/dc19-0535DOI Listing
July 2019

A Multicenter, Randomized, Placebo-Controlled Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients With Rheumatoid Arthritis.

Arthritis Rheumatol 2019 09 22;71(9):1437-1449. Epub 2019 Jul 22.

Arthritis Research UK Centre for Epidemiology, University of Manchester, and NIHR Manchester Biomedical Research Center, Manchester NHS Foundation Trust, Manchester, UK.

Objective: Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVEs in RA patients.

Methods: A randomized, double-blind, placebo-controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P < 0.05. RA patients age >50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety.

Results: A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [IQR] 1.90, 3.49 years) (7,827 patient-years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [HR] 0.66 [95% confidence interval (95% CI) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low-density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C-reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [IQR 0.94, 6.08] versus 3.60 mg/liter [IQR 1.47, 7.49]; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI -14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar.

Conclusion: Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists' Collaboration meta-analysis of statin effects in other populations.
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http://dx.doi.org/10.1002/art.40892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771601PMC
September 2019

Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes: A Secondary Analysis of 3 Randomized Clinical Trials.

JAMA Netw Open 2019 03 1;2(3):e190223. Epub 2019 Mar 1.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Importance: Acquisition of reliable randomized clinical trial evidence of the effects of cardiovascular interventions on cognitive decline is a priority.

Objectives: To estimate the association of cognitive aging with the avoidance of vascular events in cardiovascular intervention trials and understand whether reports of nonsignificant results exclude worthwhile benefit.

Design, Setting, And Participants: This secondary analysis of 3 randomized clinical trials in participants with preexisting occlusive vascular disease or diabetes included survivors to final in-trial follow-up in the Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials of lipid modification for prevention of cardiovascular events. Data were collected from February 1994 through January 2013 and analyzed from January 2015 through December 2018.

Exposures: Incident vascular events and diabetes and statin therapy.

Main Outcomes And Measures: Cognitive function was assessed at the end of a mean (SD) of 4.9 (1.5) years of follow-up using a 14-item verbal test. Associations of the incidence of vascular events and new-onset diabetes during the trials, with cognitive function at final in-trial follow-up were estimated and expressed as years of cognitive aging (using the association of the score with age >60 years). The benefit on cognitive aging mediated through the effects of lowering low-density lipoprotein cholesterol levels on events was estimated by applying these findings to nonfatal event differences observed with statin therapy in the HPS trial.

Results: Among 45 029 participants undergoing cognitive assessment, mean (SD) age was 67.9 (8.0) years; 80.7% were men. Incident stroke (n = 1197) was associated with 7.1 (95% CI, 5.7-8.5) years of cognitive aging; incident transient ischemic attack, myocardial infarction, heart failure, and new-onset diabetes were associated with 1 to 2 years of cognitive aging. In HPS, randomization to statin therapy for 5 years resulted in 2.0% of survivors avoiding a nonfatal stroke or transient ischemic attack and 2.4% avoiding a nonfatal cardiac event, which yielded an expected reduction in cognitive aging of 0.15 (95% CI, 0.11-0.19) years. With 15 926 participants undergoing cognitive assessment, HPS had 80% power to detect a 1-year (ie, 20% during the 5 years) difference in cognitive aging.

Conclusions And Relevance: The expected cognitive benefits of the effects of preventive therapies on cardiovascular events during even the largest randomized clinical trials may have been too small to be detectable. Hence, nonsignificant findings may not provide good evidence of a lack of worthwhile benefit on cognitive function with prolonged use of such therapies.

Trial Registration: isrctn.com and ClinicalTrials.gov Identifiers: ISRCTN48489393, ISRCTN74348595, and NCT00461630.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.0223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484650PMC
March 2019

Cholesteryl Ester Transfer Protein Inhibition for Preventing Cardiovascular Events: JACC Review Topic of the Week.

J Am Coll Cardiol 2019 02;73(4):477-487

Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Cholesteryl ester transfer protein (CETP) facilitates exchange of triglycerides and cholesteryl ester between high-density lipoprotein (HDL) and apolipoprotein B100-containing lipoproteins. Evidence from genetic studies that variants in the CETP gene were associated with higher blood HDL cholesterol, lower low-density lipoprotein cholesterol, and lower risk of coronary heart disease suggested that pharmacological inhibition of CETP may be beneficial. To date, 4 CETP inhibitors have entered phase 3 cardiovascular outcome trials. Torcetrapib was withdrawn due to unanticipated off-target effects that increased risk of death, and major trials of dalcetrapib and evacetrapib were terminated early for futility. In the 30,000-patient REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, anacetrapib doubled HDL cholesterol, reduced non-HDL cholesterol by 17 mg/dl (0.44 mmol/l), and reduced major vascular events by 9% over 4 years, but anaceptrapib was found to accumulate in adipose tissue, and regulatory approval is not being sought. Therefore, despite considerable initial promise, CETP inhibition provides insufficient cardiovascular benefit for routine use.
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http://dx.doi.org/10.1016/j.jacc.2018.10.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354546PMC
February 2019

Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus.

N Engl J Med 2018 10 26;379(16):1540-1550. Epub 2018 Aug 26.

Background: Increased intake of n-3 fatty acids has been associated with a reduced risk of cardiovascular disease in observational studies, but this finding has not been confirmed in randomized trials. It remains unclear whether n-3 (also called omega-3) fatty acid supplementation has cardiovascular benefit in patients with diabetes mellitus.

Methods: We randomly assigned 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease to receive 1-g capsules containing either n-3 fatty acids (fatty acid group) or matching placebo (olive oil) daily. The primary outcome was a first serious vascular event (i.e., nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, excluding confirmed intracranial hemorrhage). The secondary outcome was a first serious vascular event or any arterial revascularization.

Results: During a mean follow-up of 7.4 years (adherence rate, 76%), a serious vascular event occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.55). The composite outcome of a serious vascular event or revascularization occurred in 882 patients (11.4%) and 887 patients (11.5%), respectively (rate ratio, 1.00; 95% CI, 0.91 to 1.09). Death from any cause occurred in 752 patients (9.7%) in the fatty acid group and in 788 (10.2%) in the placebo group (rate ratio, 0.95; 95% CI, 0.86 to 1.05). There were no significant between-group differences in the rates of nonfatal serious adverse events.

Conclusions: Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo. (Funded by the British Heart Foundation and others; Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).
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http://dx.doi.org/10.1056/NEJMoa1804989DOI Listing
October 2018

Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus.

N Engl J Med 2018 10 26;379(16):1529-1539. Epub 2018 Aug 26.

Background: Diabetes mellitus is associated with an increased risk of cardiovascular events. Aspirin use reduces the risk of occlusive vascular events but increases the risk of bleeding; the balance of benefits and hazards for the prevention of first cardiovascular events in patients with diabetes is unclear.

Methods: We randomly assigned adults who had diabetes but no evident cardiovascular disease to receive aspirin at a dose of 100 mg daily or matching placebo. The primary efficacy outcome was the first serious vascular event (i.e., myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial hemorrhage). The primary safety outcome was the first major bleeding event (i.e., intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding). Secondary outcomes included gastrointestinal tract cancer.

Results: A total of 15,480 participants underwent randomization. During a mean follow-up of 7.4 years, serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group (658 participants [8.5%] vs. 743 [9.6%]; rate ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.97; P=0.01). In contrast, major bleeding events occurred in 314 participants (4.1%) in the aspirin group, as compared with 245 (3.2%) in the placebo group (rate ratio, 1.29; 95% CI, 1.09 to 1.52; P=0.003), with most of the excess being gastrointestinal bleeding and other extracranial bleeding. There was no significant difference between the aspirin group and the placebo group in the incidence of gastrointestinal tract cancer (157 participants [2.0%] and 158 [2.0%], respectively) or all cancers (897 [11.6%] and 887 [11.5%]); long-term follow-up for these outcomes is planned.

Conclusions: Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry, but it also caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard. (Funded by the British Heart Foundation and others; ASCEND Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).
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http://dx.doi.org/10.1056/NEJMoa1804988DOI Listing
October 2018

Renal and Cardiovascular Risk According to Tertiles of Urinary Albumin-to-Creatinine Ratio: The Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT).

Diabetes Care 2018 09 19;41(9):1963-1969. Epub 2018 Jul 19.

Objective: Baseline data from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) indicated that tertiles of urinary albumin-to-creatinine ratios (ACRs) in the normal range at age 10-16 years are associated with risk markers for diabetic nephropathy (DN) and cardiovascular disease (CVD). We aimed to determine whether the top ACR tertile remained associated with DN and CVD risk over the 2-4-year AdDIT study.

Research Design And Methods: One hundred fifty adolescents (mean age 14.1 years [SD 1.6]) with baseline ACR in the upper tertile (high-ACR group) recruited to the AdDIT trial, who remained untreated, and 396 (age 14.3 years [1.6]) with ACR in the middle and lower tertiles (low-ACR group), who completed the parallel AdDIT observational study, were evaluated prospectively with assessments of ACR and renal and CVD markers, combined with carotid intima-media thickness (cIMT) at baseline and end of study.

Results: After a median follow-up of 3.9 years, the cumulative incidence of microalbuminuria was 16.3% in the high-ACR versus 5.5% in the low-ACR group (log-rank < 0.001). Cox models showed independent contributions of the high-ACR group (hazard ratio 4.29 [95% CI 2.08-8.85]) and HbA (1.37 [1.10-1.72]) to microalbuminuria risk. cIMT change from baseline was significantly greater in the high- versus low-ACR group (mean difference 0.010 mm [0.079], = 0.006). Changes in estimated glomerular filtration rate, systolic blood pressure, and hs-CRP were also significantly greater in the high-ACR group ( < 0.05).

Conclusions: ACR at the higher end of the normal range at the age of 10-16 years is associated with an increased risk of progression to microalbuminuria and future CVD risk, independently of HbA.
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http://dx.doi.org/10.2337/dc18-1125DOI Listing
September 2018

Questioning the Associations of ω-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks-Reply.

JAMA Cardiol 2018 08;3(8):781-782

Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, England.

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http://dx.doi.org/10.1001/jamacardio.2018.1312DOI Listing
August 2018

Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta-Analysis.

J Am Heart Assoc 2018 05 30;7(11). Epub 2018 May 30.

School of Medicine, University of Dundee, United Kingdom

Background: Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear.

Methods And Results: We conducted a systematic review and individual participant meta-analysis to examine the effect of vitamin D supplementation on flow-mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo-controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial-level meta-analysis was performed using random-effects models; individual participant meta-analyses used a 2-stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial-level meta-analysis, and 24 trials (2051 participants) contributed to individual-participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial-level meta-analysis showed no significant effect of supplementation on macrovascular measures (flow-mediated dilatation, 0.37% [95% confidence interval, -0.23 to 0.97]; carotid-femoral pulse wave velocity, 0.00 m/s [95% confidence interval, -0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial-level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues.

Conclusions: Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis.
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http://dx.doi.org/10.1161/JAHA.117.008273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015391PMC
May 2018

Genomic Response to Vitamin D Supplementation in the Setting of a Randomized, Placebo-Controlled Trial.

EBioMedicine 2018 May 10;31:133-142. Epub 2018 Apr 10.

Wellcome Centre for Human Genetics (WHG), Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. Electronic address:

Background: Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomized trials may afford an opportunity to systematically assess molecular responses.

Methods: In the Biochemical Efficacy and Safety Trial of Vitamin D (BEST-D), a double-blind, placebo-controlled, dose-finding, randomized clinical trial, 305 community-dwelling individuals aged over 65 years were randomly allocated to treatment with vitamin D 4000 IU, 2000 IU or placebo daily for 12 months. Genome-wide genotypes at baseline, and transcriptome and plasma levels of cytokines (IFN-γ, IL-10, IL-8, IL-6 and TNF-α) at baseline and after 12 months, were measured. The trial had >90% power to detect 1.2-fold changes in gene expression.

Findings: Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D (25[OH]D, 4000 IU regimen), but had no significant effect on whole-blood gene expression (FDR < 5%) or on plasma levels of cytokines compared with placebo. In pre-specified analysis, rs7041 (intron variant, GC) had a significant effect on circulating levels of 25(OH)D in the low dose, but not in the placebo or high dose vitamin D regimen. A gene expression quantitative trait locus analysis (eQTL) demonstrated evidence of 31,568 cis-eQTLs (unique SNP-probe pairs) among individuals at baseline and 34,254 after supplementation for 12 months (any dose). No significant associations involving vitamin D supplementation response eQTLs were found.

Interpretation: We performed a comprehensive functional genomics and molecular analysis of vitamin D supplementation in a randomized, placebo-controlled trial. Although this study was limited to mostly Caucasian individuals aged over 65 years, the results differ from many previous studies and do not support a strong effect of vitamin D on long-term transcriptomic changes in blood or on plasma cytokine levels. The trial demonstrates the feasibility of applying functional genomic and genetic approaches in randomized trials to assess molecular and individual level responses.

Key Result: Supplementation with high-dose vitamin D in older people for 12 months in a randomized, placebo-controlled trial had no significant effect on gene expression or on plasma concentrations of selected cytokines.

Trial Registration: SRCTN registry (Number 07034656) and the European Clinical Trials Database (EudraCT Number 2011-005763-24).
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http://dx.doi.org/10.1016/j.ebiom.2018.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013786PMC
May 2018

ASCEND: A Study of Cardiovascular Events iN Diabetes: Characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes.

Am Heart J 2018 04 24;198:135-144. Epub 2017 Dec 24.

Clinical Trial Service Unit, Richard Doll Building, Old Road Campus, Roosevelt Drive, Headington, Oxford; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, England.

Objectives: The use of aspirin for the secondary prevention of cardiovascular disease (CVD) is firmly established, and the proportional reductions in heart attacks and strokes appear to be similar in people with and without diabetes. Uncertainty remains about the role of antiplatelet treatments for primary prevention of CVD, and guidelines vary in their recommendations. It has also been hypothesized that long-term aspirin can prevent gastro-intestinal and other cancers. Observational studies suggest associations between higher intakes of omega-3 fatty acids (FA) and lower rates of CVD, but there is no large-scale randomized evidence to support using prophylactic omega-3 FA supplementation in primary prevention. ASCEND is a randomized trial assessing whether 100 mg daily aspirin safely prevents CVD and cancer in patients with diabetes without known arterial disease. It is also assessing whether supplementation with 1 g omega-3 FA daily prevents CVD. This paper describes the methods and baseline characteristics of the randomized participants.

Methods And Results: Between 2005 and 2011, using mail-based methods, 15,480 people with diabetes were randomized to aspirin versus placebo and, in a factorial design, to omega-3 FA supplementation versus placebo. Blood and urine samples were collected to allow baseline stratification by biochemical prognostic variables (e.g. HbA1c, blood lipids). Follow-up is for a median of at least 7 years.

Conclusions: Demonstrating that prophylactic aspirin safely reduces the risk of CVD or cancer in the primary prevention setting, or that omega-3 FA supplementation prevents CVD, would be relevant to hundreds of millions of people worldwide who are currently not receiving such therapies. The results of ASCEND will be reported in 2018.
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http://dx.doi.org/10.1016/j.ahj.2017.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971211PMC
April 2018

Ezetimibe: Likely to Be Beneficial For All.

Circulation 2018 04;137(15):1583-1584

Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032819DOI Listing
April 2018

Impact of Apolipoprotein(a) Isoform Size on Lipoprotein(a) Lowering in the HPS2-THRIVE Study.

Circ Genom Precis Med 2018 02;11(2):e001696

From the Medical Research Council Population Health Research Unit (S.P., M.R.H., R.H., C.B., J.A.); and the Clinical Trial Service Unit and Epidemiological Studies Unit (S.P., J.C.H., M.R.H., E.V.-M., R.H., A.O., C.B., R.C., M.L., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.); and Center for Preventive Medicine, University of Oslo, Norway (T.R.P.). A complete list of collaborators in HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is given in reference 13.

Background: Genetic studies have shown lipoprotein(a) (Lp[a]) to be an important causal risk factor for coronary disease. Apolipoprotein(a) isoform size is the chief determinant of Lp(a) levels, but its impact on the benefits of therapies that lower Lp(a) remains unclear.

Methods: HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is a randomized trial of niacin-laropiprant versus placebo on a background of simvastatin therapy. Plasma Lp(a) levels at baseline and 1 year post-randomization were measured in 3978 participants from the United Kingdom and China. Apolipoprotein(a) isoform size, estimated by the number of kringle IV domains, was measured by agarose gel electrophoresis and the predominantly expressed isoform identified.

Results: Allocation to niacin-laropiprant reduced mean Lp(a) by 12 (SE, 1) nmol/L overall and 34 (6) nmol/L in the top quintile by baseline Lp(a) level (Lp[a] ≥128 nmol/L). The mean proportional reduction in Lp(a) with niacin-laropiprant was 31% but varied strongly with predominant apolipoprotein(a) isoform size (=4×10) and was only 18% in the quintile with the highest baseline Lp(a) level and low isoform size. Estimates from genetic studies suggest that these Lp(a) reductions during the short term of the trial might yield proportional reductions in coronary risk of ≈2% overall and 6% in the top quintile by Lp(a) levels.

Conclusions: Proportional reductions in Lp(a) were dependent on apolipoprotein(a) isoform size. Taking this into account, the likely benefits of niacin-laropiprant on coronary risk through Lp(a) lowering are small. Novel therapies that reduce high Lp(a) levels by at least 80 nmol/L (≈40%) may be needed to produce worthwhile benefits in people at the highest risk because of Lp(a).

Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00461630.
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http://dx.doi.org/10.1161/CIRCGEN.117.001696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841847PMC
February 2018

Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals.

JAMA Cardiol 2018 03;3(3):225-234

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, England.

Importance: Current guidelines advocate the use of marine-derived omega-3 fatty acids supplements for the prevention of coronary heart disease and major vascular events in people with prior coronary heart disease, but large trials of omega-3 fatty acids have produced conflicting results.

Objective: To conduct a meta-analysis of all large trials assessing the associations of omega-3 fatty acid supplements with the risk of fatal and nonfatal coronary heart disease and major vascular events in the full study population and prespecified subgroups.

Data Sources And Study Selection: This meta-analysis included randomized trials that involved at least 500 participants and a treatment duration of at least 1 year and that assessed associations of omega-3 fatty acids with the risk of vascular events.

Data Extraction And Synthesis: Aggregated study-level data were obtained from 10 large randomized clinical trials. Rate ratios for each trial were synthesized using observed minus expected statistics and variances. Summary rate ratios were estimated by a fixed-effects meta-analysis using 95% confidence intervals for major diseases and 99% confidence intervals for all subgroups.

Main Outcomes And Measures: The main outcomes included fatal coronary heart disease, nonfatal myocardial infarction, stroke, major vascular events, and all-cause mortality, as well as major vascular events in study population subgroups.

Results: Of the 77 917 high-risk individuals participating in the 10 trials, 47 803 (61.4%) were men, and the mean age at entry was 64.0 years; the trials lasted a mean of 4.4 years. The associations of treatment with outcomes were assessed on 6273 coronary heart disease events (2695 coronary heart disease deaths and 2276 nonfatal myocardial infarctions) and 12 001 major vascular events. Randomization to omega-3 fatty acid supplementation (eicosapentaenoic acid dose range, 226-1800 mg/d) had no significant associations with coronary heart disease death (rate ratio [RR], 0.93; 99% CI, 0.83-1.03; P = .05), nonfatal myocardial infarction (RR, 0.97; 99% CI, 0.87-1.08; P = .43) or any coronary heart disease events (RR, 0.96; 95% CI, 0.90-1.01; P = .12). Neither did randomization to omega-3 fatty acid supplementation have any significant associations with major vascular events (RR, 0.97; 95% CI, 0.93-1.01; P = .10), overall or in any subgroups, including subgroups composed of persons with prior coronary heart disease, diabetes, lipid levels greater than a given cutoff level, or statin use.

Conclusions And Relevance: This meta-analysis demonstrated that omega-3 fatty acids had no significant association with fatal or nonfatal coronary heart disease or any major vascular events. It provides no support for current recommendations for the use of such supplements in people with a history of coronary heart disease.
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http://dx.doi.org/10.1001/jamacardio.2017.5205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885893PMC
March 2018

Study protocol for statin web-based investigation of side effects (StatinWISE): a series of randomised controlled N-of-1 trials comparing atorvastatin and placebo in UK primary care.

BMJ Open 2017 Dec 1;7(12):e016604. Epub 2017 Dec 1.

Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: Statins are effective at preventing cardiovascular disease, widely prescribed and their use is growing. Uncertainty persists about whether they cause symptomatic muscle adverse effects, such as pain and weakness, in the absence of statin myopathy. Discrepancies between data from observational studies, which suggest statins are associated with excess muscle symptoms, and from randomised trials, which suggest no such excess, have caused confusion. N-of-1 trials offer the opportunity to establish whether muscle symptoms during statin use are caused by statins in particular individuals.

Methods And Analysis: This series of 200 randomised, double-blinded N-of-1 trials in primary care will determine (1) the effect of statins on all muscle symptoms and (2) the effect of statins on muscle pain that is perceived to be statin related. Patients who are considering discontinuing statin use due to muscle symptoms and those who have discontinued in the last 3 years due to such symptoms will be recruited. Participants will be randomised to a sequence of six 2-month treatment periods during which they will receive atorvastatin 20 mg per day or matched placebo. On each of the last 7 days of each treatment period, participants will rate their muscle symptoms on a Visual Analogue Scale (VAS).At the end of their trial, participants will be shown numerical and graphical summaries of their own symptom data during statin and placebo periods. The primary analysis on the aggregate data from all participants will be a linear mixed model for VAS muscle symptom score, comparing scores during treatment with statin and placebo.

Ethics And Dissemination: This trial received a favourable opinion from South Central-Hampshire A Research Ethics Committee. Results will be published in a peer-reviewed medical journal. Dissemination of results to patients will take place via the media, website (statinwise.lshtm.ac.uk) and patient organisations.

Trial Registration Number: ISRCTN30952488.
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http://dx.doi.org/10.1136/bmjopen-2017-016604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719321PMC
December 2017

Effects of Vitamin D on Blood Pressure, Arterial Stiffness, and Cardiac Function in Older People After 1 Year: BEST-D (Biochemical Efficacy and Safety Trial of Vitamin D).

J Am Heart Assoc 2017 Oct 24;6(10). Epub 2017 Oct 24.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom

Background: The relevance of vitamin D for prevention of cardiovascular disease is uncertain. The BEST-D (Biochemical Efficacy and Safety Trial of vitamin D) trial previously reported effects of vitamin D on plasma markers of vitamin D status, and the present report describes the effects on blood pressure, heart rate, arterial stiffness, and cardiac function.

Methods And Results: This was a randomized, double-blind, placebo-controlled trial of 305 older people living in United Kingdom, who were allocated vitamin D 4000 IU (100 μg), vitamin D 2000 IU (50 μg), or placebo daily. Primary outcomes were plasma concentrations of 25-hydroxy-vitamin D and secondary outcomes were blood pressure, heart rate, and arterial stiffness in all participants at 6 and 12 months, plasma N-terminal prohormone of brain natriuretic peptide levels in all participants at 12 months, and echocardiographic measures of cardiac function in a randomly selected subset (n=177) at 12 months. Mean (SE) plasma 25-hydroxy-vitamin D concentrations were 50 (SE 2) nmol/L at baseline and increased to 137 (2.4), 102 (2.4), and 53 (2.4) nmol/L after 12 months in those allocated 4000 IU/d, 2000 IU/d of vitamin D, or placebo, respectively. Allocation to vitamin D had no significant effect on mean levels of blood pressure, heart rate, or arterial stiffness at either 6 or 12 months, nor on any echocardiographic measures of cardiac function, or plasma N-terminal prohormone of brain natriuretic peptide concentration at 12 months.

Conclusions: The absence of any significant effect of vitamin D on blood pressure, arterial stiffness, or cardiac function suggests that any beneficial effects of vitamin D on cardiovascular disease are unlikely to be mediated through these mechanisms.

Clinical Trial Registration: URL: https://www.clinicaltrialsregister.eu/ctr-search/search. Unique identifier: EudraCT number: 2011-005763-24a.
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http://dx.doi.org/10.1161/JAHA.117.005707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721827PMC
October 2017

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors.

Lancet 2017 Nov 21;390(10110):2360-2371. Epub 2017 Sep 21.

Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Strangeways Research Laboratory, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK; British Heart Foundation Cambridge Centre for Research Excellence, Addenbrooke's Hospital, Cambridge, UK. Electronic address:

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries.

Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants.

Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59-1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69-0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76-0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39-0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups.

Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency.

Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation.
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http://dx.doi.org/10.1016/S0140-6736(17)31928-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714430PMC
November 2017

The Role of Emerging Risk Factors in Cardiovascular Outcomes.

Curr Atheroscler Rep 2017 Jun;19(6):28

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, UK.

Purpose Of Review: This review discusses the recent evidence for a selection of blood-based emerging risk factors, with particular reference to their relation with coronary heart disease and stroke.

Recent Findings: For lipid-related emerging risk factors, recent findings indicate that increasing high-density lipoprotein cholesterol is unlikely to reduce cardiovascular risk, whereas reducing triglyceride-rich lipoproteins and lipoprotein(a) may be beneficial. For inflammatory and hemostatic biomarkers, genetic studies suggest that IL-6 (a pro-inflammatory cytokine) and several coagulation factors are causal for cardiovascular disease, but such studies do not support a causal role for C-reactive protein and fibrinogen. Patients with chronic kidney disease are at high cardiovascular risk with some of this risk not mediated by blood pressure. Randomized evidence (trials or Mendelian) suggests homocysteine and uric acid are unlikely to be key causal mediators of chronic kidney disease-associated risk and sufficiently large trials of interventions which modify mineral bone disease biomarkers are unavailable. Despite not being causally related to cardiovascular disease, there is some evidence that cardiac biomarkers (e.g. troponin) may usefully improve cardiovascular risk scores. Many blood-based factors are strongly associated with cardiovascular risk. Evidence is accumulating, mainly from genetic studies and clinical trials, on which of these associations are causal. Non-causal risk factors may still have value, however, when added to cardiovascular risk scores. Although much of the burden of vascular disease can be explained by 'classic' risk factors (e.g. smoking and blood pressure), studies of blood-based emerging factors have contributed importantly to our understanding of pathophysiological mechanisms of vascular disease, and new targets for potential therapies have been identified.
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http://dx.doi.org/10.1007/s11883-017-0661-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419996PMC
June 2017